沙丁胺醇气雾剂在健康受试者体内的药物动力学和相对生物利用度

目的:研究沙丁胺醇气雾剂在健康受试者的药物动力学和生物利用度.方法:十名健康男性志愿者单剂量吸入1.2 mg沙丁胺醇气雾剂或口服沙丁胺醇水溶液.用HPLC法测定人血浆中沙丁胺醇浓度.以非房室模型计算药物动力学参数,计算气雾剂相对水溶液的生物利用度.结果:气雾剂和口服溶液的药物动力学参数如下:T_(max)(0.22±0.07)和(1.8±0.6)h,C_(max)(3.4±1.1)和(3.9±1.4)μg·L~(-1),T_(1/2)(4.5±1.5)和(4.6±1.1)h,AUC_(0-20min)(0.9±0.3)和(0.16±0.10)μg·h·L~(-1).两种给药途径的T_(max)和AUC_(0-20 min)之间差异显著(P<0.01).AUC_(0-20min)(nihal)为 AUC_(0-20 min)(po)的 8倍.沙丁胺醇气雾剂相对口服溶液的生物利用度为 57％±24％.结论:沙丁胺醇气雾剂在人体的吸收过程与口服溶液差异有显著性.     

Relative bioavailability of salbutamol to the lung following inhalation when administration is prolonged

AIMS: Urinary salbutamol post-inhalation has been shown to be an index of lung deposition. The possibility of using the urinary method for prolonged periods of inhalation (such as nebulized therapy) has been evaluated. METHODS: On separate study days volunteers received salbutamol 5 x 100 microg via either oral administration (ORAL), oral with 5 g oral charcoal (ORAL + C), inhaled from a metered dose inhaler (MDI) or MDI plus 5 g oral charcoal (MDI + C). Each dose was separated by 2 min, i.e. administration time of 8 min. Urine samples were provided at 0, 30, 40, 60 and 120 min postdose. Also seven subjects inhaled 5x100 microg doses from the MDI on five separate occasions and provided urine 0-30 min post dose. RESULTS: No salbutamol was detected in urine samples following ORAL + C. The mean (s.d.) amounts of salbutamol excreted in the urine in the first 30 min post ORAL, MDI and MDI + C were 0.42 (0.55), 11.01 (3.77) and 11.60 (3.68) microg, respectively. The ratio of urinary salbutamol following MDI and MDI + C to ORAL in the 0-30 min collection period was 26.2 and 27.8, and between 30 and 40 min postdose was 5.1 and 4.7, respectively. There was no difference between urinary salbutamol over the first 30 min following MDI and MDI + C with a mean ratio (90% confidence interval) of 95.6 (84.0, 107.2). The mean (s.d.) coefficient of variation for the 30 min urinary salbutamol elimination following inhalation of 5 x 100 microg doses from the MDI by seven subjects (on 5 separate study days) was 9.4 (2.3)%. CONCLUSIONS: The 30 min urinary salbutamol method can be used for an inhalation period of up to 8 min to identify the relative bioavailability to the lung. Samples taken after this time period are affected by excretion of the oral absorbed fraction. Most nebulisers deliver their dose within this administration time.     

In vitro performance of two common valved holding chambers with a chlorofluorocarbon-free beclomethasone metered-dose inhaler

STUDY OBJECTIVE: To compare in vitro aerosol deposition from a beclomethasone dipropionate metered-dose inhaler (MDI) containing hydrofluoroalkane propellant with that of the MDI in combination with two common valved holding chambers (VHCs) to evaluate how these VHCs affect the respirable dose of beclomethasone dipropionate. DESIGN: In vitro aerosol deposition study. SETTING: University research center. DEVICES: Beclomethasone dipropionate hydrofluoroalkane MDI alone, the MDI with OptiChamber VHC, and the MDI with AeroChamber-Plus VHC. INTERVENTION: The respirable dose (1-5-microm aerosol particles) of beclomethasone dipropionate was determined by sampling 10 80-microg actuations from five runs with each configuration (MDI alone, MDI with OptiChamber, and MDI with AeroChamber-Plus), using a well-established in vitro cascade impactor method. MEASUREMENTS AND MAIN RESULTS: Beclomethasone dipropionate aerosol was washed from the impactor with 50% methanol and quantified by means of high-performance liquid chromatography. Differences among outcomes were determined by using analysis of variance. Mean beclomethasone dipropionate respirable dose from AeroChamber-Plus (27.2 +/- 10.0 microg/actuation) was not significantly different (p>0.05) from that of the MDI alone (29.0 +/- 7.0 microg/actuation). OptiChamber respirable dose (12.8 +/- 6.0 microg/actuation) was less than half that produced by either the AeroChamber-Plus or the MDI alone (p=0.013). CONCLUSIONS: The OptiChamber and AeroChamber-Plus VHCs do not demonstrate equivalent in vitro performance when used with a beclomethasone dipropionate MDI that contains hydrofluoroalkane propellant. The respirable dose of beclomethasone dipropionate aerosol from the hydrofluoroalkane MDI was decreased by only 6% when the MDI was mated to an AeroChamber-Plus VHC and by 56% when used with an OptiChamber VHC.     

In vitro performance characteristics of valved holding chamber and spacer devices with a fluticasone metered-dose inhaler

STUDY OBJECTIVE: To compare the in vitro aerosol deposition characteristics of several commercially available valved holding chamber (VHC) and spacer devices used with a fluticasone metered-dose inhaler (MDI). DESIGN: In vitro aerosol deposition study SETTING: University-affiliated research center. DEVICES: Seven VHC devices: BreatheRite, E-Z Spacer, EasiVent, AeroChamber, InspirEase, OptiChamber, and Space Chamber. Six spacer devices: OptiHaler, Aerosol Cloud Enhancer (ACE), Gentle-Haler, MediSpacer, Ellipse, and a 6-inch tube (1-inch inside diameter). INTERVENTION: The respirable dose (aerosol particles 1-5 microm) of fluticasone was determined by sampling 10 220-microg actuations from five runs with each spacer or VHC plus MDI combination, by using a well-established in vitro cascade impactor method. MEASUREMENTS AND MAIN RESULTS: Fluticasone aerosol was washed from the impactor with methanol and quantified by means of high-performance liquid chromatography. Differences among outcomes were determined with analysis-of-variance testing. Among spacers, Ellipse had the highest respirable dose (104 microg, p < 0.01). Respirable doses for the 6-inch tube (74.3 microg), Gentle-Haler (81.7 microg), and MediSpacer (82.6 microg) were no different from that of the MDI (p > 0.05), whereas respirable doses of OptiHaler (44.6 microg) and ACE (47.2 microg) were less than those of all other spacers (p < 0.001). Among VHC devices, respirable doses from EasiVent (35.6 microg), AeroChamber (47.0 microg), InspirEase (52.7 microg), OptiChamber (53.1 microg), and Space Chamber (58.3 microg) were not different (p > 0.05), whereas BreatheRite (13.1 microg) and E-Z Spacer (27.3 microg) respirable doses were less than those of the other VHC devices (p < 0.05). CONCLUSION: Spacers and VHC devices available in the United States do not demonstrate equivalent in vitro performance with the fluticasone MDI. The difference between highest and lowest respirable doses in each device category would likely lead to clinically relevant differences in the quantity of fluticasone delivered to a patient.     

Relative lung and total systemic bioavailability following inhalation from a metered dose inhaler compared with a metered dose inhaler attached to a large volume plastic spacer and a jet nebuliser

OBJECTIVE: To compare the lung and systemic delivery of salbutamol following inhalation from a metered dose inhaler (MDI), a MDI attached to a spacer (MDI+SP) and a nebuliser (NEB) using a urinary pharmacokinetic method. METHOD: Twelve healthy subjects each provided urine samples at 0, 30 min and pooled up to 24 h after the start of 5 x 100 microg salbutamol inhaled from MDI and MDI + SP and after 2.5 mg was delivered by NEB. Following nebulisation, the amount of salbutamol trapped on an exhalation filter together with that remaining in the apparatus was determined. The amount left in the spacer and that leaving the MDI mouthpiece was also determined. Thus, for all the methods, the amount available for inhalation from each study dose was determined. RESULTS: The mean (+/- SD) 30-min urinary excretion amounts of salbutamol for MDI, MDI+SP and NEB were 12.6+/-3.5, 27.1+/-6.0 and 16.1+/-4.6 microg, respectively. The mean ratios (90% confidence intervals) for MDI+SP compared with MDI and NEB were 230.2 (186.7, 273.8) and 183.0 (146.4, 219.7) (both P values<0.001), respectively, while that between MDI and NEB was 134 (110.4, 159.1) (P < 0.05). The mean (+/-SD) 24-h urinary excretion values for salbutamol and its metabolite were 287.0+/-46.5, 198.1+/-34.7 and 253.4+/-138.3 microg, respectively. Following inhalation a mean of 202.9+/-51.5 microg was left in the spacer. Similarly, after nebulisation 1387.7+/-88.9 microg was left in the nebuliser chamber, 26.3+/-8.0 microg in the mouthpiece and 553.8+/-68.5 microg exhaled. The mean emitted dose from the MDI was 88.4+/-6.1 microg per actuation. When normalised for the amounts available for inhalation, the mean amounts of salbutamol excreted in the urine during the first 30 min were 2.86+/-0.78, 9.15+/-1.69 and 3.06+/-0.70% following MDI, MDI + SP and NEB, respectively. CONCLUSION: Five 100-microg doses inhaled from a metered dose inhaler attached to a spacer delivered more to the lungs and less to the systemic circulation than either the same doses from a metered dose inhaler used alone or five times the dose given via a jet nebuliser. Spacers should be routinely used instead of nebulisers to manage patients unless they are short of breath.     

Two-dimensional and three-dimensional imaging show ciclesonide has high lung deposition and peripheral distribution: a nonrandomized study in healthy volunteers.

Drug deposition is an important factor that contributes to safety and efficacy outcomes of inhaled steroid therapy. Ciclesonide is a nonhalogenated, inhaled corticosteroid under investigation for the treatment of asthma. Therefore, this study was performed to assess lung deposition of ciclesonide. Technetium-99m (99mTc)-labeled ciclesonide (where the 99mTc-label is physically dissolved in the ciclesonide-hydrofluoroalkane [HFA] solution aerosol) inhaled by healthy volunteers was analyzed by two-dimensional (2-D) and three-dimensional (3-D) imaging to determine lung deposition. Six healthy volunteers inhaled one puff of 40 microg (exactuator, equivalent to 50 microg ex-valve) ciclesonide for 2-D imaging, and two healthy volunteers inhaled 10 puffs of 40 microg ciclesonide for 2-D and 3-D imaging. The ciclesonide aerosol was administered via metered-dose inhaler (MDI) containing HFA-134a as propellant. The ex-actuator mean (+/- standard deviation) deposition of ciclesonide in the lungs was higher (52% +/- 11%) than in the mouth/pharynx (38% +/- 14%). Two-dimensional and 3-D imaging showed that ciclesonide reached all regions of the lung. Mean percent deposition in peripheral regions (47% and 34%) was higher than in lower central regions (17% and 30%), as revealed by 3-D and 2-D imaging, respectively. Inhalation of up to 400 microg of ciclesonide produced no drug-related side effects. In conclusion, ciclesonide administered via metered-dose inhaler using HFA-134a as a propellant provided high lung deposition (>50%), greater distribution throughout peripheral regions of the lungs, and relatively low oropharyngeal deposition.     

Determination of the relative bioavailability of salbutamol to the lungs and systemic circulation following nebulization

AIMS: Clinical studies comparing nebulized drug delivery systems could be flawed because of the high doses used. We have compared lung and total systemic delivery of salbutamol from a nebuliser with that from a metered dose inhaler by measuring urinary recovery of drug and its sulphate metabolite. METHODS: Twelve healthy volunteers provided urine samples at 0, 0.5, 1, 2, 4, 8, 12 and 24 h after the start of dosing. Formulations and doses were 5 x 100 microg oral solution (ORAL), 5 x 100 microg from a metered dose inhaler (MDI), 2.5 mg using a nebuliser (NEB) and NEB with 25 g oral charcoal (NEBC). Each study phase was separated by 7 days and the order of dosing was randomized. RESULTS: Mean (s.d.) 30 min urinary salbutamol excretion after ORAL, MDI, NEB and NEBC was 0.4 (0.7), 12.1 (3.7), 15.0 (3.9) and 18.2 (5.7) microg, respectively (all P<0.001 compared with ORAL). When normalized for the dose available for inhalation from MDI, NEB and NEBC, the mean (s.d.) 30 min urinary excretion of salbutamol was 2.4 (0.7), 2.9 (0.6) and 2.7 (0.6)%, respectively, with a mean ratio (90% confidence interval) between NEB and NEBC, of 95.3 (91.1, 99.5)%. The mean (s.d.) excretion of salbutamol plus its metabolite over 24 h post ORAL, MDI, NEB and NEBC dosing was 297.9 (38.3), 290.3 (41.4), 266.5 (44.6) and 151.7 (40.9) microg, respectively. The mean ratio (90% confidence interval) between MDI and ORAL, and NEB and ORAL were 97.5 (94.1, 101.0) and 90.7 (81.2, 100.2)%, respectively. The NEBC data indicate that 6.07 (1.04)% of the nominal nebulized dose was delivered to the lungs. CONCLUSIONS: The 30 min urinary recovery of salbutamol, an index of the relative systemic bioavailability of salbutamol following inhalation, can be used to compare the lung deposition of nebulized systems. Similarly, the urinary 24 h recovery of salbutamol plus its metabolite, an index of the relative systemic bioavailability of salbutamol following inhalation, can be used to compare the delivery of nebulized drug to the systemic circulation.     

Novolizer: a multidose dry powder inhaler

Novolizer is a multidose breath-actuated dry powder inhaler (DPI) approved for use with salbutamol (albuterol) and budesonide. It has multiple patient feedback mechanisms and an inspiratory flow rate threshold designed to optimise dosage. In two studies, children aged 4-11 years with asthma correctly used Novolizer and generated mean peak inspiratory flow rates (PIFRs) through Novolizer of 76 and 92.7 L/min, well above the Novolizer threshold of 35-50 L/min. In healthy volunteers, median lung deposition of budesonide administered via Novolizer was 19.9-32.1% at mean PIFRs of 54-99 L/min. In a randomised, double-blind, single-dose study in patients with chronic obstructive pulmonary disease (COPD) and asthma, the 1-hour improvement from baseline in mean maximum forced expiratory volume in 1 second (FEV(1)) was 21.3% with inhalation of salbutamol through Novolizer, and 19.5% through Sultanol pressurised metered-dose inhaler (MDI). FEV(1) increased significantly in patients with asthma and COPD treated for 4 weeks in a randomised, open-label comparison of salbutamol through either Novolizer or Sultanol MDI. A randomised open-label study in adults with asthma treated with inhaled budesonide found equivalent improvements in FEV(1) and symptoms with Novolizer and Turbuhaler. Novolizer was well accepted overall. Most patients preferred it to previously used MDIs or DPIs. Only 4-5% found the taste feedback unacceptable. Physicians observed improved compliance over 4 weeks in 80% of patients with asthma using Novolizer.     

Selecting an accessory device with a metered-dose inhaler: variable influence of accessory devices on fine particle dose, throat deposition, and drug delivery with asynchronous actuation from a metered-dose inhaler.

Accessory devices reduce common problems with metered-dose inhalers (MDIs), namely high oropharyngeal deposition of aerosol and incoordination between actuation and inhalation by the patient. The objective of this study was to systematically compare the performance of various accessory devices in vitro. MDIs were tested alone or in combination with four spacers (Toilet paper roll, Ellipse, Optihaler, Myst Assist) and five holding chambers (Aerochamber, Optichamber, Aerosol Cloud Enhancer, Medispacer, and Inspirease). An Anderson cascade impactor was used to measure aerosol mass median aerodynamic diameter (MMAD) and fine particle dose (MMAD < 4.7 microm). In separate experiments, the influence of asynchronous MDI actuation on drug delivery was determined with a simulated spontaneous breathing model. Compared with the MDI alone, all of the accessory devices reduced aerosol MMAD and increased lung-throat ratio (fine particle dose/throat impaction; p < 0.05 for both parameters). The fine particle dose of albuterol was 40% higher with the Ellipse (p < 0.01), was equivalent with the Toilet Paper Roll, Aerochamber, Optichamber, and Medispacer, and was 33-56% lower with the Optihaler, Myst Assist, Aerosol Cloud Enhancer, and Inspirease (p < 0.03). MDI actuation in synchrony with inspiration produced highest drug delivery; when MDI actuation occurred 1-sec before inspiration or during exhalation, decrease in drug delivery with holding chambers (10-40% reduction) was less than that with spacers (40-90% reduction). Accessory device selection is complicated by variability in performance between devices, and in the performance of each device in different clinical settings. In vitro characterization of a MDI and accessory device could guide appropriate device selection in various clinical settings.     

Studies on the bronchodilator,tremorogenic, cardiovascular and hypokalaemic effects of fenoterol dry powder in asthma

1. The airway and tremor response and cardiovascular and hypokalaemic effects of single and cumulative doses of fenoterol given by dry powder capsules (DPC) and by metered dose inhaler (MDI) were studied in asthmatics in two randomized, crossover trials. 2. Single doses of fenoterol DPC and MDI (0.2 mg, 0.4 mg), investigated in 24 subjects, produced similar, dose-dependent increases in FEV1. Fenoterol DPC caused less tremor response and less hypokalaemic effects than fenoterol MDI. 3. Cumulative doses of fenoterol DPC and MDI (0.2, 0.6, 1.4, 3.0, 6.2 mg), investigated in 12 subjects, produced a comparable bronchodilatation (mean maximum increase in FEV1 was 0.53 +/- 0.06/0.52 +/- 0.081 for DPC/MDI) and a similar, dose-dependent rise in heart rate (35 +/- 3.81/41 +/- 2.25 beats min(-1)). The rise in tremor and the fall in plasma potassium were smaller after DPC than after MDI. The mean maximum changes were 51.58 +/- 6.41/95.83 +/- 6.75 cm s(-2) for tremor and -0.68 +/- 0.09/-0.96 +/- 0.10 mmol l(-1) for potassium. 4. Our findings may result from a difference in the pharmacokinetics of the dry powder and the aerosol formulation, particularly differences in distribution and absorption. 5. In conclusion, fenoterol DPC used in low therapeutic doses (0.2,0.4 mg), is preferable to the MDI. Fenoterol DPC used as rescue medication in high cumulative doses, do not suggest a greater safety margin than the MDI and the same restrictions should be considered for the fenoterol dry powder formulation as suggested for the MDI.     

Balloon-Based In Vitro MDI Aerosol Deposition Experiments on the Effects of Mouthpiece Diameter

For this article, we studied the effects of mouthpiece diameter and flow rate on aerosol penetration efficiency for metered-dose inhaler (MDI) applications. Measurements show that increasing the mouthpiece diameter has a moderate and positive influence on the particle penetration efficiency of the MDI. The particle penetration efficiency increases monotonically with the increase of the mouthpiece diameter from 16 mm to 20 mm. Second, the experiments show that airflow rate has an apparent and significant effect on particles deposition in the oral airway. The reduction of the airflow rate from 90 L/min to 30 L/min tripled the penetration efficiency of the MDI. A new experimental system has been employed to measure the particles deposition in the human airways. Expansion balloons were used to induce airflow as well as to collect the penetrated particles through an airway cast. The potential advantages of the balloon-based experimental system are simplicity, accuracy, and cost-effectiveness.     

Balloon-based in vitro MDI aerosol deposition experiments on the effects of mouthpiece diameter

For this article, we studied the effects of mouthpiece diameter and flow rate on aerosol penetration efficiency for metered-dose inhaler (MDI) applications. Measurements show that increasing the mouthpiece diameter has a moderate and positive influence on the particle penetration efficiency of the MDI. The particle penetration efficiency increases monotonically with the increase of the mouthpiece diameter from 16 mm to 20 mm. Second, the experiments show that airflow rate has an apparent and significant effect on particles deposition in the oral airway. The reduction of the airflow rate from 90 L/min to 30 L/min tripled the penetration efficiency of the MDI. A new experimental system has been employed to measure the particles deposition in the human airways. Expansion balloons were used to induce airflow as well as to collect the penetrated particles through an airway cast. The potential advantages of the balloon-based experimental system are simplicity, accuracy, and cost-effectiveness.     

Systemic beta-adrenoceptor responses to salbutamol given by metered-dose inhaler alone and with pear shaped spacer attachment: comparison of electrocardiographic, hypokalaemic and haemodynamic effects.

1. Seven normal subjects were given cumulative doubling doses of inhaled salbutamol either by metered-dose inhaler (MDI) alone, or in conjunction with a pear shaped spacer attachment (PSS). Dose increments were made every 20 min from 100 micrograms to 2000 micrograms. 2. Plasma potassium (K), electrocardiographic (ECG) and haemodynamic (HR, SBP and DBP) responses were measured at each dose increment. 3. There were falls in K (as mean and 95% CI) in response to salbutamol (P less than 0.001): 3.70 mmol l-1 (3.46-3.95) to 3.20 mmol l-1 (2.91-3.49) MDI, 3.78 mmol l-1 (3.61-3.95) to 3.18 mmol l-1 (3.06-3.30) PSS. 4. Salbutamol produced marked ECG effects including T wave flattening (P less than 0.001): 0.46 mV (0.24-0.68) to 0.22 mV (0.07-0.37) MDI, 0.50 mV (0.23-0.77) to 0.24 mV (0.07-0.41) PSS; and Q-Tc interval prolongation (P less than 0.001): 0.382 s (0.372-0.392) to 0.409 s (0.397-0.421) MDI, 0.378 s (0.358-0.398) to 0.410 s (0.388-0.432) PSS. U waves occurred in five subjects with MDI and in four with PSS. S-T segment depression was present in two subjects with MDI and in three with PSS. These changes were not however associated with ventricular extrasystoles. There were also significant chronotropic effects (P less than 0.001): 63 beats min-1 (57-70) to 79 beats min-1 (69-89) MDI, 58 beats min-1 (53-63) to 75 beats min-1 (69-81) PSS. 5. Comparison of dose-response curves for MDI alone and with PSS showed no significant differences, for any of the variables measured.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical efficacy of two beta 2-sympathicomimetics in different inhalers in children with asthma. Comparison of pirbuterol in a breath-actuated inhaler and salbutamol in a customary metered-dose inhaler.

In a controlled clinical crossover trial, the therapeutic effect of pirbuterol (CAS 38677-81-5) in the Autohaler was compared to that of salbutamol in a customary metered-dose aerosol in 17 children with asthma. Each child was randomized to both treatments with a washout period of at least 1 day and at most 13 days. Ten children commenced with salbutamol and then switched over to pirbuterol, and the other 7 vice versa. The main criterion to evaluate efficacy was the forced expiratory volume after 1 s (FEV1). Other efficacy criteria were forced vital capacity (FVC) and peak expiratory flow (PEF). The patients were given detailed instructions on how to use the inhalers. Each treatment was applied in the morning with one shot (0.2 mg pirbuterol or 0.1 mg salbutamol). FEV1, FVC and PEF were measured in all patients 10 min before and 10 min after medication with the whole-body plethysmograph; further measurements were carried out in most patients 60 and 240 min after application. There was a mean increase of 47% in the FEV1 compared to baseline with pirbuterol in the Autohaler compared to a mean increase of only 30% with salbutamol in the customary metered-dose inhaler. The difference is statistically significant (p = 0.036). A linear crossover analysis showed a significant treatment effect 10 min after application in favour of pirbuterol with no significant period effects or interactions (p = 0.020). The increases of FVC and PEF after pirbuterol treatment were also remarkably higher than after salbutamol. No side effects were observed.     

The dose-related hyper-and-hypokalaemic effects of salbutamol and its arrhythmogenic potential.

1. The hypokalaemic effect of salbutamol after more than 30 min of administration has been well described. A hyper-and-hypokalaemic effect for adrenaline has been reported, but no such hyperkalaemic effect for salbutamol. 2. The possible hyper-and-hypokalaemic effects of salbutamol with the concomitant potential for pro-arrhythmia were assessed in the baboon (Papio ursinus). 3. Male and female baboons were anaesthetized with ketamine (15 mg kg-1) and maintained with 6% pentobarbitone as spontaneously breathing animals. Six baboons in each group received either 10, 100 or 500 micrograms kg-1 salbutamol i.v. Lead II of the ECG and femoral i.a. blood pressure were recorded continuously for 10 min. Arterial blood samples were collected at 0 min and then after 3 and 10 min of salbutamol administration. 4. All the animals developed sinus tachycardia (above 200 beats min-1) within 30 s of each dose of salbutamol administration and the high heart rate persisted throughout the experiment. All the animals were hyperkalaemic after 3 min and hypokalaemic after 10 min for each dose of salbutamol. Left ventricular conduction defects were seen in 3 animals during the hyperkalaemic phase. No arrhythmia was seen during the hypokalaemic phase. 5. Salbutamol has a transient hyperkalaemic and a more prolonged hypokalaemic effect in the baboon. The hypokalaemia could not be associated with arrhythmia although conduction defects were associated with the hyperkalaemia. 6. Since salbutamol is used as a bronchodilator in asthmatic patients and to treat acute hyperkalaemia, it is suggested that caution should be exercised when using salbutamol in high doses to treat acute asthma especially during the first few minutes of administration. The finding of hyperkalaemia with salbutamol questions its use in the treatment of hyperkalaemia.     

Particle size and charge distribution analysis of pharmaceutical aerosols generated by inhalers

Aerosol particles generated by inhalers for respiratory drug delivery acquire electrostatic charge during the dispersion process. The electrostatic charge distribution of the particles can affect the efficiency of drug delivery by influencing both the transport and deposition of inhaled particles in the human lung. To analyze the electrostatic charge acquired by the aerosol particles, two sets of metered-dose inhaler (MDI) and dry powder inhaler (DPI) devices were investigated. Both the particle size and charge distributions were measured simultaneously by using an electrical single-particle aerodynamic relaxation time (E-SPART) analyzer. The analyzer was calibrated with particles of known size, which were generated by a vibrating orifice aerosol generator (TSI Inc.) and charge using the Faraday cup method. The charge distributions of the pharmaceutical aerosols from both the DPI and MDI devices were bipolar in nature. Although the net charge-to-mass ratio was less than 0.2 microC/g, the individual particles were charged with a relatively high charge: -2 to + 2 microC/g. The count mean aerodynamic diameter of the aerosols generated from these devices was 3-5 microm.     

Aerosol delivery of amphotericin B desoxycholate (Fungizone) and liposomal amphotericin B (AmBisome): aerosol characteristics and in-vivo amphotericin B deposition in rats

In the treatment or prophylaxis of invasive pulmonary aspergillosis, it may be attractive to administer the antifungal agent amphotericin directly to the pulmonary route via aerosol inhalation. In this study, we describe the aerosol characteristics of aerosolized nonliposomal amphotericin B (Fungizone) and liposomal amphotericin B (AmBisome), and the in-vivo aerosol deposition. Aerosols were generated with a Collison nebulizer. Aerosol amphotericin concentrations and mass median diameters were measured. In-vivo pulmonary deposition was evaluated by measuring amphotericin concentrations in lungs of treated rats. Whole body aerosol deposition was determined by measuring radioactivity in tissues of rats after treatment with radiolabelled liposomes. For Fungizone and AmBisome, aerosol amphotericin concentrations were 24.5+/-4.9 and 23.8+/-3.0 microg L(-1), respectively. The values for the median mass diameter were 1.38 and 2.26 microm for Fungizone and 2.43 and 1.97 microm for AmBisome. Amphotericin concentrations in lungs after 60-min nebulization of Fungizone or AmBisome were 24.2+/-6.4 and 21.7+/-2.6 microg g(-1), respectively. After nebulization of radiolabelled liposomes, no radioactivity was retrieved from tissues other than the lungs or the gastrointestinal tract. Nebulization of either Fungizone or AmBisome leads to respirable aerosols and results in a substantial lung tissue concentration of amphotericin and low systemic exposure of amphotericin B. Aerosol administration of either Fungizone or AmBisome may be an attractive approach to prevent or treat pulmonary aspergillosis.     

Acute systemic effects of inhaled salbutamol in asthmatic subjects expressing common homozygous beta2-adrenoceptor haplotypes at positions 16 and 27

AIMS: The relationship between beta2-adrenoceptor polymorphisms at positions 16 and 27, and the acute systemic beta2-adrenoceptor effects of inhaled salbutamol is unclear. We therefore elected to evaluate the influence of common homozygous beta2-adrenoceptor haplotypes on the acute systemic beta2-adrenoceptor effects following inhaled salbutamol in asthmatic subjects. METHODS: An initial database search of 531 asthmatic subjects identified the two commonest homozygous haplotypes at positions 16 and 27 to be Arg16-Gln27 (12%) and Gly16-Glu27 (19%). After a 1-week washout period where all beta2-adrenoceptor agonists were withdrawn, 16 Caucasian subjects (Arg16-Gln27: n = 8 and Gly16-Glu27: n = 8) were given a single dose of inhaled salbutamol (1200 microg), followed by serial blood sampling for serum potassium, along with measurements of diastolic blood pressure and heart rate, at 5-min intervals for 20 min. RESULTS: The two groups were well matched for age, sex, FEV1, and inhaled corticosteroid dose. Baseline values for serum potassium, diastolic blood pressure and heart rate were not significantly different comparing Arg16-Gln27 vs Gly16-Glu27. The mean +/- SEM maximum serum potassium change from baseline over 20 min was significantly greater (P = 0.04) for Arg16-Gln27: -0.37 +/- 0.05 mmol l(-1) vs Gly16-Glu27: -0.23 +/- 0.04 mmol l(-1); 95% CI for difference: -0.01 to -0.28 mmol l(-1). The maximum diastolic blood pressure change from baseline over 20 min was significantly greater (P = 0.0008) for Arg16-Gln27: -13 +/- 1 mmHg vs Gly16-Glu27: -4 +/- 2 mmHg; 95% CI for difference: -5, 14 mmHg. There was no significant difference comparing the maximum heart rate change from baseline for Arg16-Gln27: 10 +/- 3 beats min(-1) vs Gly16-Glu27: 10 +/- 3 beats min(-1). CONCLUSIONS: Caucasian asthmatic subjects with the Arg16-Gln27 haplotype exhibited a greater systemic response to inhaled salbutamol, compared with those with the Gly16-Glu27 haplotype. The attenuated beta2-adrenoceptor response in the Gly16-Glu27 haplotype would be in keeping with increased susceptibility to prior down-regulation by endogenous catecholamines.     

Hypokalaemia and other non-bronchial effects of inhaled fenoterol and salbutamol: a placebo-controlled dose-response study in healthy volunteers.

1. The hypokalaemia-inducing effects of two widely used inhaled antiasthmatic beta 2-adrenoceptor agonists, fenoterol and salbutamol, were compared in six healthy male volunteers. 2. Each drug was administered in three different doses, 400, 600 and 800 micrograms, which were repeated three times with 30 min intervals (total doses 1200, 1800 and 2400 micrograms in 1 h). The treatments were given at 1 week intervals in random order in a single-blind fashion. 3. The concentration of potassium in plasma was dose-dependently reduced by both drugs with peak effects 75-90 min after the first inhalations. The hypokalaemic effect of fenoterol was significantly greater than that of equal doses of salbutamol (average +/- s.d. reductions of 1.13 +/- 0.32 and 0.67 +/- 0.25 mEq l-1, respectively, after the highest doses, P less than 0.05). Concomitantly, decreases were noted in the amplitude of the T-wave on the ECG. 4. The concentration of cyclic AMP in plasma was measured and used as an indicator of systemic beta 2-adrenoceptor agonistic effects of the drugs. Increases in cAMP were a close mirror image of the drugs' effects on potassium in plasma. 5. Plasma renin activity, noradrenaline in plasma and heart rate were also dose-dependently increased by the treatments, whereas blood pressure remained unaltered. 6. While the clinical significance of hypokalaemia induced by inhaled beta 2-adrenoceptor sympathomimetics still is a matter of debate, our results point to possible differences between therapeutically equipotent doses of fenoterol and salbutamol in their propensity to cause hypokalaemia and other acute non-bronchial effects.     

A comparison of the extent and duration of hypokalaemia following three nebulized beta2-adrenoceptor agonists

Summary The hypokalaemic effects of equal doses (5 mg) of fenoterol, salbutamol, terbutaline and an equal volume of saline administered by nebulization were compared in eight healthy subjects. Plasma potassium was measured at 15-min intervals for 60 min and at 90 min, 2, 4 and 6 h following administration.Fenoterol, salbutamol and terbutaline all significantly decreased plasma potassium when compared to saline; however, the magnitude and duration of this effect differed between the active agents. Both fenoterol and terbutaline significantly reduced plasma potassium for 4 h whereas salbutamol was only different from 30 to 120 min. The maximum decrease occurred with fenoterol (–0.78 mmol/l), followed by terbutaline (–0.70 mmol/l) and salbutamol (–0.33 mmol/l). Both terbutaline and fenoterol had a significantly greater effect compared with salbutamol.When administered by nebulization fenoterol and terbutaline are likely to have a greater hypokalaemic effect then salbutamol and this effect is likely to be more long lasting.